This project utilizes a novel murine model to study immune processes that influence metastasis of intraocular melanoma. Intraocular melanoma (uveal melanoma) is the most common intraocular tumor in adults and has an incidence of 7 cases per million adults per year in the Caucasian population. Up to 50% of the uveal melanoma patients die from metastatic disease with the liver being the organ most frequently affected. Approximately 90% of patients who die from uveal melanoma have liver metastases at the time of death. Unfortunately, the long-term survival of uveal melanoma patients has not improved in over 35 years and to date there is no effective therapy for liver metastases of uveal melanoma. A compelling body of evidence suggests that elements of the innate immune system, namely natural killer (NK) cells, have an important impact on the development of liver metastasis and mortality in uveal melanoma patients. Recent findings from our laboratory have shown that liver metastases arising from intraocular melanomas induce NKT cells in the liver to suppress the anti-metastatic function of hepatic NK cells. Accordingly, Specific Aim #1 will characterize the molecules and mechanisms by which liver NKT cells suppress NK cell-mediated resistance to liver metastases of intraocular melanomas. Preliminary results from other experiments strongly suggest that neutrophils contribute to the resistance to the metastasis of intraocular melanomas, possibly by activating NK cells. The novel role neutrophils in contributing to the resistance to ocular tumor metastases will be explored. Other investigations in Specific Aim #1 will test strategies for reversing NKT cell-mediated suppression of NK cells and thereby reducing metastatic disease in intraocular-bearing hosts. Uveal melanoma, like most cancers, is a disease of aging with 61 years being the median age for uveal melanoma patients. Preliminary studies indicate that aging mice have more severe liver metastases than young mice and that this exacerbation of metastatic disease is reversed by depleting tumor-infiltrating macrophages. With this in mind, Specific Aim #2 will examine the role of aging on metastases arising from intraocular melanomas and develop strategies for restoring the aging host's resistance to metastatic disease.